Method for treating cervical cancer

ABSTRACT

Use of Interleukin-20 for treating cervical cancer or cells infected with human papilloma virus. IL-20 can be administered alone or in conjunction with radiation or chemotherapeutic agents or surgical excision of the involved cells or lesions.

[0001] This claims the benefit under 35 U.S.C. §119 (e) of U.S.Provisional Application No. 60/341,783 filed on Dec. 17, 2001.

BACKGROUND OF THE INVENTION

[0002] According to the American Cancer Society, 12,800 new cases ofinvasive cervical cancer would be diagnosed in the United States in1999. During the same year, 4800 patients were expected to die of thedisease. This represents approximately 1.8% of all cancer deaths inwomen and 18% of gynecological cancer deaths. However, for women aged 20to 39 years of age, cervical cancer is the second leading cause ofcancer deaths. Molecular and epidemiologic studies have demonstrated astrong relationship between human papillomavirus (HPV), cervicalintraepithelial neoplasia, (CIN), and invasive carcinoma of the cervix.Thus, there is a need to develop new therapeutic entities for thetreatment of human papillomavirus infection, cervical intraepithelialneoplasia and carcinoma of the cervix.

DESCRIPTION OF THE INVENTION

[0003] The present invention fills this need by administeringinterleukin-20 (IL-20) to a mammalian having cervical cancer. IL-20 canalso be used to treat a human papillomavirus infection. The presentinvention also provides a method for inhibiting the growth of cervicalcancer cells by bringing IL-20 into contact with said cancerous cervicalcells. Interleukin-20 (formally called Zcyto10) can be producedaccording to the method described in International Patent ApplicationNo. PCT/US98/25228 filed on Nov. 25, 1998. The human IL-20 polypeptideis comprised of a sequence of 176 amino acids with the initial Met asshown in SEQ ID NO: 1 and SEQ ID NO:2. It is believed that aminoresidues 1-24 are signal sequence, and the mature IL-20 polypeptide isrepresented by the amino acid sequence comprised of residues 25, aleucine, through amino acid residue 176, a glutamic acid residue, alsodefined by SEQ ID NO:12. Another embodiment of the present invention isdefined by the sequences of SEQ ID NO: 3 and SEQ ID NO: 4. Thepolypeptide of SEQ ID NO: 4 is comprised of 151 amino acid residueswherein amino acids 1-24 comprise a signal sequence and the maturesequence is comprised of amino acid residues 25, a leucine, throughamino acid 151 a glutamic acid, also defined by SEQ ID NO: 13. Anotheractive variant is comprised of amino acid residues 33, a cysteine,through amino acid residue 176 of SEQ ID NO:2. This variant is alsodefined by SEQ ID NO:26.

[0004] Mouse IL-20 is also a polypeptide comprised of 176 amino acidresidues as defined by SEQ ID NOs: 18 and 19. Mouse IL-20 has a signalsequence extending from amino acid residue 1, a methionine, extending toand including amino acid residue 24, a glycine of SEQ ID NO: 19. Thus,the mature mouse IL-20 extends from amino acid residue 25, a leucine, toand including amino acid residue 176 a leucine of SEQ ID NO: 19, alsodefined by SEQ ID NO:20. Another active variant is believed to extendfrom amino acid 33, a cysteine, through amino acid 176, of SEQ ID NO:19. This variant is also defined by SEQ ID NO:25.

[0005] A variant of mouse IL-20 is defined by SEQ ID NOs: 33 and 34.This variant is 154 amino acid residues in length and has a signalsequence extending from amino acid residue 1, a methionine, to andincluding amino acid residue 24, a glycine, of SEQ ID NO:34. Thus, themature sequence extends from amino acid residue 25, a leucine, to andincluding amino acid residue 154, a leucine, of SEQ ID NO:34. The maturesequence is also defined by SEQ ID NO:35.

Pathology of Cervical Cancer

[0006] Cervical dysplasia cells and cervical intraepithelial neoplasia(CIN) cells develop into invasive cervical cancer over a number ofyears. CIN grades I, II and III correspond to mild, moderate, and severecervical dysplasia. CIN III, which includes severe dysplasia andcarcinoma in situ, is unlikely to regress spontaneously and, ifuntreated, may eventually penetrate the basement membrane, becominginvasive carcinoma. Squamous cell carcinoma accounts for 80 to 85% ofall cervical cancers; adenocarcinomas account for most of the rest.Invasive cervical cancer usually spreads by direct extension intosurrounding tissues and the vagina or via the lymphatics to the pelvicand para-aortic lymph nodes drained by the cervix. Hematologic spread ispossible.

Symptoms, Signs and Diagnosis of Cervical Cancer

[0007] CIN is usually asymptomatic and discovered because of an abnormalPap smear. Patients with early-stage cervical cancer usually presentwith irregular vaginal bleeding, which is most often postcoital, butintermenstrual bleeding or menometrorrhagia may occur. Patients withlarger cervical cancers or advanced-stage disease may present withfoul-smelling vaginal discharge, abnormal vaginal bleeding, or pelvicpain. Obstructive uropathy, back pain, and leg swelling aremanifestations of late-stage disease. Suspicious lesions, generallyfirst detected by a Pap smear are biopsied. If clinical disease isinvasive, staging is performed on the basis of the physical examination,with a metastatic survey including cystoscopy, sigmoidoscopy, IVpyelography, chest x-ray, and skeletal x-rays.

Treatment of Cervical Cancer with IL-20

[0008] Cervical cancer can be treated by administration of IL-20 to afemale mammal, particularly a human female, afflicted with the disease.IL-20 can be administered intralesionally, or intramuscularly forlocalized disease. For metastatic disease, IL-20 can also beadministered by intraperitoneal administration including intravenousadministration. IL-20 can be administered alone or in conjunction withstandard therapies such as surgery, radiation or other chemotherapeuticagents such as bleomycin, chlorambucil, epirubicin, 5-fluorouracil,ifosfamide, mitomycin, methotrexate, vincristine, cisplatin andvinblastine.

Use of Interleukin-20 to Treat Cells Infected with the HumanPapillomavirus/Genital Warts

[0009] Cells infected with the human papillomavirus (HPV) can be treatedwith IL-20 to inhibit the proliferation of the virus. Anogenital wartscaused by HPV type 6, 11, 16, 18, 31, 33 and 35 are transmitted sexuallyand have an incubation period of 1 to 6 months. Endocervical wartinfections caused by type 16 or 18 have been implicated as a cause ofcervical intraepithelial neoplasia and cervical cancer. HPV types 16 and18 generally do no not cause external genital warts, which are usuallycaused by types 6 and 1.

Symptoms, Signs and Diagnosis

[0010] Genital warts usually appear as soft, moist, minute pink or graypolyps that enlarge, may become pedunculated, and are usually found inclusters. The surfaces resemble the surface of cauliflower. In men theyoccur most commonly on warm, moist surfaces in the subpreputial area, onthe coronal sulcus, within the urethral meatus, and on the penile shaft.In women, the vulva, the vaginal wall, the cervix, and the perineum maybecome involved. They are particularly common in the perianal region andrectum in homosexual men. Growth rates vary, but pregnancy,immunosuppression, or maceration of the skin may accelerate both thegrowth of individual lesions and their spread. Genital warts usually canbe identified by their appearance but must be differentiated from theflat-topped condyloma lata of secondary syphilis. Biopsies of a typicalor persistent warts may be necessary to exclude carcinoma.

[0011] IL-20 can be administered directly into lesions containing cellsinfected with HPV alone or with standard therapies such as interferonalpha or interferon beta both of which are commercially available.Interferon alpha is available from Schering Corporation of Kenilworth,N.J. and is called INTRON A®. Interferon beta is produced by Biogen ofCambridge, Mass. and is called AVONEX ®. IL-20 can also be administeredwith other standard therapies for treating HPV including antimitoticssuch as podophyllotoxin, podophyllin, or 5-fluorouracil; caustics suchas trichloroacetic acid; or interferon inducers such as imiquimod.

[0012] The quantities of IL-20 for effective therapy will depend uponmany different factors, including means of administration, target site,physiological state of the patient, and other medications administered.Thus, treatment dosages should be titrated to optimize safety andefficacy. Typically, dosages used in vitro may provide useful guidancein the amounts useful for in vivo administration of these reagents.Animal testing of effective doses for treatment of particular disorderswill provide further predictive indication of human dosage. Methods foradministration include, intravenous, peritoneal, intramuscular, orintralesional. Pharmaceutically acceptable carriers will include water,saline, buffers to name just a few. Dosage ranges would ordinarily beexpected from 1 μg to 1000%g per kilogram of body weight per day.However, the doses may be higher or lower as can be determined by amedical doctor with ordinary skill in the art. Excipients andstabilizers can possible be added. These include glycine, histidine,glutamate, aspartate, sugars, sucrose, trehalose, galactose sorbitol,arginine, D-and/or L0amino acids, sugar alcohols, lactose, maltose,threonine, lysine, methionine, isoleucine, a surface active agent suchas TWEEN 80, TWEEN 20, polyethylene glycol (PEG) (particularly thosePEGs having molecular weights between 1000 and 35000 Da), cetyl alcohol,polyvinylpyrrolidone, polyvinyl alcohol, lanolin alcohol and sorbitan. Areducing agent may be included, such as cysteine, N-acetyl-cysteine, andthioglycerol. For a complete discussion of drug formulations and dosageranges see Remington's Pharnaceutical Sciences,18^(th) Ed., (MackPublishing Co., Easton, Penn., 1996), and Goodman and Gilman's: ThePharmacological Bases of Therapeutics, 9^(th) Ed. (Pergamon Press 1996).

[0013] IL-20 can also me administered in conjunction with othertreatments for cervical cancer such as radiation and chemotherapy.Examples of chemotherapeutic agents include bleomycin, chlorambucil,epirubicin, 5-fluorouracil, ifosfamide, mitomycin, methotrexate,vincristine, cisplatin and vinblastine.

EXAMPLE

[0014] We tested IL-20 in a HeLa299 cytotoxicity assay to measure theability of IL-20 to prevent cells from growing during normal growthconditions. We used MTT reagent (Promega, Madison, USA) as our detectionand readout for this cell inhibition assay. Procedure of a cytoxicityassay:

[0015] Day 1—Plate cells out in complete growth media (with serum) at5000 cells/well in a 96 well format and let them incubate overnight at37 degrees and 5% CO2.

[0016] Day 2—Dump off media and add a dose response of appropriateligands in complete growth media (IL-20, zmda1, and MDA7 at 10, 100, and1000 ng/ml.), along with a positive control retinoic acid (100 uM) incomplete growth media, while leaving some wells in complete growth mediaas controls of how the cells normally grow under normal conditions. Putthe cells in incubator and let the assay go for 72 hrs.

[0017] Day 5—Add 15 ul/well of MTT reagent, let cells inc. for 4 hrs.,then add 100 ul of stop solution, let cells inc. for an additional 1hr., then read the plate on a multilabel counter (Victor2, PerkinElmerLife Sciences Inc., Boston). The MTT protocol will give you tworeadings, one at a 650 wavelength (background) and one at a 572wavelength. Subtract the 650 reading from the 572 reading to get youractual output. These numbers are averaged and converted to a %inhibition value.

[0018] Results:

[0019] Retnoic acid gave a 53% inhibition of growth (positive control)

[0020] IL-20 gave a maximal 20% inhibition of growth

1 43 1 926 DNA Homo sapiens CDS (45)...(572) 1 ctttgaattc ctagctcctgtggtctccag atttcaggcc taag atg aaa gcc tct 56 Met Lys Ala Ser 1 agt cttgcc ttc agc ctt ctc tct gct gcg ttt tat ctc cta tgg act 104 Ser Leu AlaPhe Ser Leu Leu Ser Ala Ala Phe Tyr Leu Leu Trp Thr 5 10 15 20 cct tccact gga ctg aag aca ctc aat ttg gga agc tgt gtg atc gcc 152 Pro Ser ThrGly Leu Lys Thr Leu Asn Leu Gly Ser Cys Val Ile Ala 25 30 35 aca aac cttcag gaa ata cga aat gga ttt tct gac ata cgg ggc agt 200 Thr Asn Leu GlnGlu Ile Arg Asn Gly Phe Ser Asp Ile Arg Gly Ser 40 45 50 gtg caa gcc aaagat gga aac att gac atc aga atc tta agg agg act 248 Val Gln Ala Lys AspGly Asn Ile Asp Ile Arg Ile Leu Arg Arg Thr 55 60 65 gag tct ttg caa gacaca aag cct gcg aat cga tgc tgc ctc ctg cgc 296 Glu Ser Leu Gln Asp ThrLys Pro Ala Asn Arg Cys Cys Leu Leu Arg 70 75 80 cat ttg cta aga ctc tatctg gac agg gta ttt aaa aac tac cag acc 344 His Leu Leu Arg Leu Tyr LeuAsp Arg Val Phe Lys Asn Tyr Gln Thr 85 90 95 100 cct gac cat tat act ctccgg aag atc agc agc ctc gcc aat tcc ttt 392 Pro Asp His Tyr Thr Leu ArgLys Ile Ser Ser Leu Ala Asn Ser Phe 105 110 115 ctt acc atc aag aag gacctc cgg ctc tgt cat gcc cac atg aca tgc 440 Leu Thr Ile Lys Lys Asp LeuArg Leu Cys His Ala His Met Thr Cys 120 125 130 cat tgt ggg gag gaa gcaatg aag aaa tac agc cag att ctg agt cac 488 His Cys Gly Glu Glu Ala MetLys Lys Tyr Ser Gln Ile Leu Ser His 135 140 145 ttt gaa aag ctg gaa cctcag gca gca gtt gtg aag gct ttg ggg gaa 536 Phe Glu Lys Leu Glu Pro GlnAla Ala Val Val Lys Ala Leu Gly Glu 150 155 160 cta gac att ctt ctg caatgg atg gag gag aca gaa taggaggaaa 582 Leu Asp Ile Leu Leu Gln Trp MetGlu Glu Thr Glu 165 170 175 gtgatgctgc tgctaagaat attcgaggtc aagagctccagtcttcaata cctgcagagg 642 aggcatgacc ccaaaccacc atctctttac tgtactagtcttgtgctggt cacagtgtat 702 cttatttatg cattacttgc ttccttgcat gattgtctttatgcatcccc aatcttaatt 762 gagaccatac ttgtataaga tttttgtaat atctttctgctattggatat atttattagt 822 taatatattt atttattttt tgctattaat gtatttaattttttacttgg gcatgaaact 882 ttaaaaaaaa ttcacaagat tatatttata acctgactagagca 926 2 176 PRT Homo sapiens 2 Met Lys Ala Ser Ser Leu Ala Phe SerLeu Leu Ser Ala Ala Phe Tyr 1 5 10 15 Leu Leu Trp Thr Pro Ser Thr GlyLeu Lys Thr Leu Asn Leu Gly Ser 20 25 30 Cys Val Ile Ala Thr Asn Leu GlnGlu Ile Arg Asn Gly Phe Ser Asp 35 40 45 Ile Arg Gly Ser Val Gln Ala LysAsp Gly Asn Ile Asp Ile Arg Ile 50 55 60 Leu Arg Arg Thr Glu Ser Leu GlnAsp Thr Lys Pro Ala Asn Arg Cys 65 70 75 80 Cys Leu Leu Arg His Leu LeuArg Leu Tyr Leu Asp Arg Val Phe Lys 85 90 95 Asn Tyr Gln Thr Pro Asp HisTyr Thr Leu Arg Lys Ile Ser Ser Leu 100 105 110 Ala Asn Ser Phe Leu ThrIle Lys Lys Asp Leu Arg Leu Cys His Ala 115 120 125 His Met Thr Cys HisCys Gly Glu Glu Ala Met Lys Lys Tyr Ser Gln 130 135 140 Ile Leu Ser HisPhe Glu Lys Leu Glu Pro Gln Ala Ala Val Val Lys 145 150 155 160 Ala LeuGly Glu Leu Asp Ile Leu Leu Gln Trp Met Glu Glu Thr Glu 165 170 175 3793 DNA Homo sapiens CDS (45)...(497) 3 ctttgaattc ctagctcctg tggtctccagatttcaggcc taag atg aaa gcc tct 56 Met Lys Ala Ser 1 agt ctt gcc ttc agcctt ctc tct gct gcg ttt tat ctc cta tgg act 104 Ser Leu Ala Phe Ser LeuLeu Ser Ala Ala Phe Tyr Leu Leu Trp Thr 5 10 15 20 cct tcc act gga ctgaag aca ctc aat ttg gga agc tgt gtg atc gcc 152 Pro Ser Thr Gly Leu LysThr Leu Asn Leu Gly Ser Cys Val Ile Ala 25 30 35 aca aac ctt cag gaa atacga aat gga ttt tct gac ata cgg ggc agt 200 Thr Asn Leu Gln Glu Ile ArgAsn Gly Phe Ser Asp Ile Arg Gly Ser 40 45 50 gtg caa gcc aaa gat gga aacatt gac atc aga atc tta agg agg act 248 Val Gln Ala Lys Asp Gly Asn IleAsp Ile Arg Ile Leu Arg Arg Thr 55 60 65 gag tct ttg caa gac aca aag cctgcg aat cga tgc tgc ctc ctg cgc 296 Glu Ser Leu Gln Asp Thr Lys Pro AlaAsn Arg Cys Cys Leu Leu Arg 70 75 80 cat ttg cta aga ctc tat ctg gac agggta ttt aaa aac tac cag acc 344 His Leu Leu Arg Leu Tyr Leu Asp Arg ValPhe Lys Asn Tyr Gln Thr 85 90 95 100 cct gac cat tat act ctc cgg aag atcagc agc ctc gcc aat tcc ttt 392 Pro Asp His Tyr Thr Leu Arg Lys Ile SerSer Leu Ala Asn Ser Phe 105 110 115 ctt acc atc aag aag gac ctc cgg ctctgt ctg gaa cct cag gca gca 440 Leu Thr Ile Lys Lys Asp Leu Arg Leu CysLeu Glu Pro Gln Ala Ala 120 125 130 gtt gtg aag gct ttg ggg gaa cta gacatt ctt ctg caa tgg atg gag 488 Val Val Lys Ala Leu Gly Glu Leu Asp IleLeu Leu Gln Trp Met Glu 135 140 145 gag aca gaa taggaggaaa gtgatgctgctgctaagaat attcgaggtc 537 Glu Thr Glu 150 aagagctcca gtcttcaatacctgcagagg aggcatgacc ccaaaccacc atctctttac 597 tgtactagtc ttgtgctggtcacagtgtat cttatttatg cattacttgc ttccttgcat 657 gattgtcttt atgcatccccaatcttaatt gagaccatac ttgtataaga tttttgtaat 717 atctttctgc tattggatatatttattagt taatatattt atttattttt tgctattaat 777 gtatttaatt ttttac 793 4151 PRT Homo sapiens 4 Met Lys Ala Ser Ser Leu Ala Phe Ser Leu Leu SerAla Ala Phe Tyr 1 5 10 15 Leu Leu Trp Thr Pro Ser Thr Gly Leu Lys ThrLeu Asn Leu Gly Ser 20 25 30 Cys Val Ile Ala Thr Asn Leu Gln Glu Ile ArgAsn Gly Phe Ser Asp 35 40 45 Ile Arg Gly Ser Val Gln Ala Lys Asp Gly AsnIle Asp Ile Arg Ile 50 55 60 Leu Arg Arg Thr Glu Ser Leu Gln Asp Thr LysPro Ala Asn Arg Cys 65 70 75 80 Cys Leu Leu Arg His Leu Leu Arg Leu TyrLeu Asp Arg Val Phe Lys 85 90 95 Asn Tyr Gln Thr Pro Asp His Tyr Thr LeuArg Lys Ile Ser Ser Leu 100 105 110 Ala Asn Ser Phe Leu Thr Ile Lys LysAsp Leu Arg Leu Cys Leu Glu 115 120 125 Pro Gln Ala Ala Val Val Lys AlaLeu Gly Glu Leu Asp Ile Leu Leu 130 135 140 Gln Trp Met Glu Glu Thr Glu145 150 5 253 DNA Homo sapiens 5 ctttgaattc ctagctcctg tggtctccagatttcaggcc taagatgaaa gcctctagtc 60 ttgccttcag ccttctctct gctgcgttttatctcctatg gactccttcc actggactga 120 agacactcaa tttgggaagc tgtgtgatcgccacaaacct tcaggaaata cgaaatggat 180 tttctgagat acggggcagt gtgcaagccaaagatggaaa cattgacatc agaatcttaa 240 ggaggactga gtc 253 6 24 DNA Homosapiens 6 attcctagct cctgtggtct ccag 24 7 25 DNA Homo sapiens 7ctctgctgcg ttttatctcc tatgg 25 8 22 DNA Homo sapiens 8 tcccaaattgagtgtcttca gt 22 9 45 DNA Homo sapiens 9 cacagcttcc caaattgagtgtcttcagtc cagtggaagg agtcc 45 10 747 DNA Homo sapiens 10 ttttctgacatacggggcag tgtgcaagcc aaagatggaa acattgacat cagaatctta 60 aggaggactgagtctttgca agacacaaag cctgcgaatc gatgctgcct cctgcgccat 120 ttgctaagactctatctgga cagggtattt aaaaactacc agacccctga ccattatact 180 ctccggaagatcagcagcct cgccaattcc tttcttacca tcaagaagga cctccggctc 240 tgtcatgcccacatgacatg ccattgtggg gaggaagcaa tgaagaaata cagccagatt 300 ctgagtcactttgaaaagct ggaacctcag gcagcagttg tgaaggcttt gggggaacta 360 gacattcttctgcaatggat ggaggagaca gaataggagg aaagtgatgc tgctgctaag 420 aatattcgaggtcaagagct ccagtcttca atacctgcag aggaggcatg accccaaacc 480 accatctctttactgtacta gtcttgtgct ggtcacagtg tatcttattt atgcattact 540 tgcttccttgcatgattgtc tttatgcatc cccaatctta attgagacca tacttgtata 600 agatttttgtaatatctttc tgctattgga tatatttatt agttaatata tttatttatt 660 ttttgctattaatgtattta attttttact tgggcatgaa actttaaaaa aaattcacaa 720 gattatatttataacctgac tagagca 747 11 614 DNA Homo sapiens 11 ttttctgaca tacggggcagtgtgcaagcc aaagatggaa acattgacat cagaatctta 60 aggaggactg agtctttgcaagacacaaag cctgcgaatc gatgctgcct cctgcgccat 120 ttgctaagac tctatctggacagggtattt aaaaactacc agacccctga ccattatact 180 ctccggaaga tcagcagcctcgccaattcc tttcttacca tcaagaagga cctccggctc 240 tgtctggaac ctcaggcagcagttgtgaag gctttggggg aactagacat tcttctgcaa 300 tggatggagg agacagaataggaggaaagt gatgctgctg ctaagaatat tcgaggtcaa 360 gagctccagt cttcaatacctgcagaggag gcatgacccc aaaccaccat ctctttactg 420 tactagtctt gtgctggtcacagtgtatct tatttatgca ttacttgctt ccttgcatga 480 ttgtctttat gcatccccaatcttaattga gaccatactt gtataagatt tttgtaatat 540 ctttctgcta ttggatatatttattagtta atatatttat ttattttttg ctattaatgt 600 atttaatttt ttac 614 12152 PRT Homo sapiens 12 Leu Lys Thr Leu Asn Leu Gly Ser Cys Val Ile AlaThr Asn Leu Gln 1 5 10 15 Glu Ile Arg Asn Gly Phe Ser Asp Ile Arg GlySer Val Gln Ala Lys 20 25 30 Asp Gly Asn Ile Asp Ile Arg Ile Leu Arg ArgThr Glu Ser Leu Gln 35 40 45 Asp Thr Lys Pro Ala Asn Arg Cys Cys Leu LeuArg His Leu Leu Arg 50 55 60 Leu Tyr Leu Asp Arg Val Phe Lys Asn Tyr GlnThr Pro Asp His Tyr 65 70 75 80 Thr Leu Arg Lys Ile Ser Ser Leu Ala AsnSer Phe Leu Thr Ile Lys 85 90 95 Lys Asp Leu Arg Leu Cys His Ala His MetThr Cys His Cys Gly Glu 100 105 110 Glu Ala Met Lys Lys Tyr Ser Gln IleLeu Ser His Phe Glu Lys Leu 115 120 125 Glu Pro Gln Ala Ala Val Val LysAla Leu Gly Glu Leu Asp Ile Leu 130 135 140 Leu Gln Trp Met Glu Glu ThrGlu 145 150 13 127 PRT Homo sapiens 13 Leu Lys Thr Leu Asn Leu Gly SerCys Val Ile Ala Thr Asn Leu Gln 1 5 10 15 Glu Ile Arg Asn Gly Phe SerAsp Ile Arg Gly Ser Val Gln Ala Lys 20 25 30 Asp Gly Asn Ile Asp Ile ArgIle Leu Arg Arg Thr Glu Ser Leu Gln 35 40 45 Asp Thr Lys Pro Ala Asn ArgCys Cys Leu Leu Arg His Leu Leu Arg 50 55 60 Leu Tyr Leu Asp Arg Val PheLys Asn Tyr Gln Thr Pro Asp His Tyr 65 70 75 80 Thr Leu Arg Lys Ile SerSer Leu Ala Asn Ser Phe Leu Thr Ile Lys 85 90 95 Lys Asp Leu Arg Leu CysLeu Glu Pro Gln Ala Ala Val Val Lys Ala 100 105 110 Leu Gly Glu Leu AspIle Leu Leu Gln Trp Met Glu Glu Thr Glu 115 120 125 14 15 PRT Homosapiens 14 Ile Ala Thr Asn Leu Gln Glu Ile Arg Asn Gly Phe Ser Asp Ile 15 10 15 15 15 PRT Homo sapiens 15 Leu Asp Arg Val Phe Lys Asn Tyr GlnThr Pro Asp His Tyr Thr 1 5 10 15 16 15 PRT Homo sapiens 16 Leu Ala AsnSer Phe Leu Thr Ile Lys Lys Asp Leu Arg Leu Cys 1 5 10 15 17 15 PRT Homosapiens 17 Val Val Lys Ala Leu Gly Glu Leu Asp Ile Leu Leu Gln Trp Met 15 10 15 18 824 DNA Mus musculus CDS (71)...(598) 18 tgggagacatcgatagccct gattgatctc tttgaatttt cgcttctggt ctccaggatc 60 taggtgtaag atgaaa ggc ttt ggt ctt gcc ttt gga ctg ttc tcc gct 109 Met Lys Gly Phe GlyLeu Ala Phe Gly Leu Phe Ser Ala 1 5 10 gtg ggt ttt ctt ctc tgg act ccttta act ggg ctc aag acc ctc cat 157 Val Gly Phe Leu Leu Trp Thr Pro LeuThr Gly Leu Lys Thr Leu His 15 20 25 ttg gga agc tgt gtg att act gca aaccta cag gca ata caa aag gaa 205 Leu Gly Ser Cys Val Ile Thr Ala Asn LeuGln Ala Ile Gln Lys Glu 30 35 40 45 ttt tct gag att cgg gat agt gtg caagct gaa gat aca aat att gac 253 Phe Ser Glu Ile Arg Asp Ser Val Gln AlaGlu Asp Thr Asn Ile Asp 50 55 60 atc aga att tta agg acg act gag tct ttgaaa gac ata aag tct ttg 301 Ile Arg Ile Leu Arg Thr Thr Glu Ser Leu LysAsp Ile Lys Ser Leu 65 70 75 gat agg tgc tgc ttc ctt cgt cat cta gtg agattc tat ctg gac agg 349 Asp Arg Cys Cys Phe Leu Arg His Leu Val Arg PheTyr Leu Asp Arg 80 85 90 gta ttc aaa gtc tac cag acc cct gac cac cat accctg aga aag atc 397 Val Phe Lys Val Tyr Gln Thr Pro Asp His His Thr LeuArg Lys Ile 95 100 105 agc agc ctc gcc aac tcc ttt ctt atc atc aag aaggac ctc tca gtc 445 Ser Ser Leu Ala Asn Ser Phe Leu Ile Ile Lys Lys AspLeu Ser Val 110 115 120 125 tgt cat tct cac atg gca tgt cat tgt ggg gaagaa gca atg gag aaa 493 Cys His Ser His Met Ala Cys His Cys Gly Glu GluAla Met Glu Lys 130 135 140 tac aac caa att ctg agt cac ttc ata gag ttggaa ctt cag gca gcg 541 Tyr Asn Gln Ile Leu Ser His Phe Ile Glu Leu GluLeu Gln Ala Ala 145 150 155 gtg gta aag gct ttg gga gaa cta ggc att cttctg aga tgg atg gag 589 Val Val Lys Ala Leu Gly Glu Leu Gly Ile Leu LeuArg Trp Met Glu 160 165 170 gag atg cta tagatgaaag tggagaggct gctgagaacactcctgtcca 638 Glu Met Leu 175 agaatctcag acctcagcac catgaagacatggccccagg tgctggcatt tctactcaag 698 agttccagtc ctcagcacca cgaagatggcctcaaaccac cacccctttg tgatataact 758 tagtgctagc tatgtgtata ttatttctacattattggct cccttatgtg aatgccttca 818 tgtgtc 824 19 176 PRT Mus musculus19 Met Lys Gly Phe Gly Leu Ala Phe Gly Leu Phe Ser Ala Val Gly Phe 1 510 15 Leu Leu Trp Thr Pro Leu Thr Gly Leu Lys Thr Leu His Leu Gly Ser 2025 30 Cys Val Ile Thr Ala Asn Leu Gln Ala Ile Gln Lys Glu Phe Ser Glu 3540 45 Ile Arg Asp Ser Val Gln Ala Glu Asp Thr Asn Ile Asp Ile Arg Ile 5055 60 Leu Arg Thr Thr Glu Ser Leu Lys Asp Ile Lys Ser Leu Asp Arg Cys 6570 75 80 Cys Phe Leu Arg His Leu Val Arg Phe Tyr Leu Asp Arg Val Phe Lys85 90 95 Val Tyr Gln Thr Pro Asp His His Thr Leu Arg Lys Ile Ser Ser Leu100 105 110 Ala Asn Ser Phe Leu Ile Ile Lys Lys Asp Leu Ser Val Cys HisSer 115 120 125 His Met Ala Cys His Cys Gly Glu Glu Ala Met Glu Lys TyrAsn Gln 130 135 140 Ile Leu Ser His Phe Ile Glu Leu Glu Leu Gln Ala AlaVal Val Lys 145 150 155 160 Ala Leu Gly Glu Leu Gly Ile Leu Leu Arg TrpMet Glu Glu Met Leu 165 170 175 20 152 PRT Mus musculus 20 Leu Lys ThrLeu His Leu Gly Ser Cys Val Ile Thr Ala Asn Leu Gln 1 5 10 15 Ala IleGln Lys Glu Phe Ser Glu Ile Arg Asp Ser Val Gln Ala Glu 20 25 30 Asp ThrAsn Ile Asp Ile Arg Ile Leu Arg Thr Thr Glu Ser Leu Lys 35 40 45 Asp IleLys Ser Leu Asp Arg Cys Cys Phe Leu Arg His Leu Val Arg 50 55 60 Phe TyrLeu Asp Arg Val Phe Lys Val Tyr Gln Thr Pro Asp His His 65 70 75 80 ThrLeu Arg Lys Ile Ser Ser Leu Ala Asn Ser Phe Leu Ile Ile Lys 85 90 95 LysAsp Leu Ser Val Cys His Ser His Met Ala Cys His Cys Gly Glu 100 105 110Glu Ala Met Glu Lys Tyr Asn Gln Ile Leu Ser His Phe Ile Glu Leu 115 120125 Glu Leu Gln Ala Ala Val Val Lys Ala Leu Gly Glu Leu Gly Ile Leu 130135 140 Leu Arg Trp Met Glu Glu Met Leu 145 150 21 16 PRT Mus musculus21 Ile Thr Ala Asn Leu Gln Ala Ile Gln Lys Glu Phe Ser Glu Ile Arg 1 510 15 22 15 PRT Mus musculus 22 Leu Asp Arg Val Phe Lys Val Tyr Gln ThrPro Asp His His Thr 1 5 10 15 23 15 PRT Mus musculus 23 Leu Ala Asn SerPhe Leu Ile Ile Lys Lys Asp Leu Ser Val Cys 1 5 10 15 24 15 PRT Musmuculus 24 Val Val Lys Ala Leu Gly Glu Leu Gly Ile Leu Leu Arg Trp Met 15 10 15 25 144 PRT Mus muculus 25 Cys Val Ile Thr Ala Asn Leu Gln AlaIle Gln Lys Glu Phe Ser Glu 1 5 10 15 Ile Arg Asp Ser Val Gln Ala GluAsp Thr Asn Ile Asp Ile Arg Ile 20 25 30 Leu Arg Thr Thr Glu Ser Leu LysAsp Ile Lys Ser Leu Asp Arg Cys 35 40 45 Cys Phe Leu Arg His Leu Val ArgPhe Tyr Leu Asp Arg Val Phe Lys 50 55 60 Val Tyr Gln Thr Pro Asp His HisThr Leu Arg Lys Ile Ser Ser Leu 65 70 75 80 Ala Asn Ser Phe Leu Ile IleLys Lys Asp Leu Ser Val Cys His Ser 85 90 95 His Met Ala Cys His Cys GlyGlu Glu Ala Met Glu Lys Tyr Asn Gln 100 105 110 Ile Leu Ser His Phe IleGlu Leu Glu Leu Gln Ala Ala Val Val Lys 115 120 125 Ala Leu Gly Glu LeuGly Ile Leu Leu Arg Trp Met Glu Glu Met Leu 130 135 140 26 144 PRT Homosapiens 26 Cys Val Ile Ala Thr Asn Leu Gln Glu Ile Arg Asn Gly Phe SerAsp 1 5 10 15 Ile Arg Gly Ser Val Gln Ala Lys Asp Gly Asn Ile Asp IleArg Ile 20 25 30 Leu Arg Arg Thr Glu Ser Leu Gln Asp Thr Lys Pro Ala AsnArg Cys 35 40 45 Cys Leu Leu Arg His Leu Leu Arg Leu Tyr Leu Asp Arg ValPhe Lys 50 55 60 Asn Tyr Gln Thr Pro Asp His Tyr Thr Leu Arg Lys Ile SerSer Leu 65 70 75 80 Ala Asn Ser Phe Leu Thr Ile Lys Lys Asp Leu Arg LeuCys His Ala 85 90 95 His Met Thr Cys His Cys Gly Glu Glu Ala Met Lys LysTyr Ser Gln 100 105 110 Ile Leu Ser His Phe Glu Lys Leu Glu Pro Gln AlaAla Val Val Lys 115 120 125 Ala Leu Gly Glu Leu Asp Ile Leu Leu Gln TrpMet Glu Glu Thr Glu 130 135 140 27 38 PRT Homo sapiens 27 Cys Gly GluGlu Ala Met Lys Lys Tyr Ser Gln Ile Leu Ser His Phe 1 5 10 15 Glu LysLeu Glu Pro Gln Ala Ala Val Val Lys Ala Leu Gly Glu Leu 20 25 30 Asp IleLeu Leu Gln Trp 35 28 71 PRT Homo sapiens 28 Ile Ala Thr Asn Leu Gln GluIle Arg Asn Gly Phe Ser Asp Ile Arg 1 5 10 15 Gly Ser Val Gln Ala LysAsp Gly Asn Ile Asp Ile Arg Ile Leu Arg 20 25 30 Arg Thr Glu Ser Leu GlnAsp Thr Lys Pro Ala Asn Arg Cys Cys Leu 35 40 45 Leu Arg His Leu Leu ArgLeu Tyr Leu Asp Arg Val Phe Lys Asn Tyr 50 55 60 Gln Thr Pro Asp His TyrThr 65 70 29 92 PRT Homo sapiens 29 Ile Ala Thr Asn Leu Gln Glu Ile ArgAsn Gly Phe Ser Asp Ile Arg 1 5 10 15 Gly Ser Val Gln Ala Lys Asp GlyAsn Ile Asp Ile Arg Ile Leu Arg 20 25 30 Arg Thr Glu Ser Leu Gln Asp ThrLys Pro Ala Asn Arg Cys Cys Leu 35 40 45 Leu Arg His Leu Leu Arg Leu TyrLeu Asp Arg Val Phe Lys Asn Tyr 50 55 60 Gln Thr Pro Asp His Tyr Thr LeuArg Lys Ile Ser Ser Leu Ala Asn 65 70 75 80 Ser Phe Leu Thr Ile Lys LysAsp Leu Arg Leu Cys 85 90 30 82 PRT Homo sapiens 30 Leu Asp Arg Val PheLys Asn Tyr Gln Thr Pro Asp His Tyr Thr Leu 1 5 10 15 Arg Lys Ile SerSer Leu Ala Asn Ser Phe Leu Thr Ile Lys Lys Asp 20 25 30 Leu Arg Leu CysHis Ala His Met Thr Cys His Cys Gly Glu Glu Ala 35 40 45 Met Lys Lys TyrSer Gln Ile Leu Ser His Phe Glu Lys Leu Glu Pro 50 55 60 Gln Ala Ala ValVal Lys Ala Leu Gly Glu Leu Asp Ile Leu Leu Gln 65 70 75 80 Trp Met 3136 PRT Homo sapiens 31 Leu Asp Arg Val Phe Lys Asn Tyr Gln Thr Pro AspHis Tyr Thr Leu 1 5 10 15 Arg Lys Ile Ser Ser Leu Ala Asn Ser Phe LeuThr Ile Lys Lys Asp 20 25 30 Leu Arg Leu Cys 35 32 61 PRT Homo sapiens32 Leu Ala Asn Ser Phe Leu Thr Ile Lys Lys Asp Leu Arg Leu Cys His 1 510 15 Ala His Met Thr Cys His Cys Gly Glu Glu Ala Met Lys Lys Tyr Ser 2025 30 Gln Ile Leu Ser His Phe Glu Lys Leu Glu Pro Gln Ala Ala Val Val 3540 45 Lys Ala Leu Gly Glu Leu Asp Ile Leu Leu Gln Trp Met 50 55 60 33756 DNA Mus musculus CDS (71)...(532) 33 tgggagacat cgatagccctgattgatctc tttgaatttt cgcttctggt ctccaggatc 60 taggtgtaag atg aaa ggcttt ggt ctt gcc ttt gga ctg ttc tcc gct 109 Met Lys Gly Phe Gly Leu AlaPhe Gly Leu Phe Ser Ala 1 5 10 gtg ggt ttt ctt ctc tgg act cct tta actggg ctc aag acc ctc cat 157 Val Gly Phe Leu Leu Trp Thr Pro Leu Thr GlyLeu Lys Thr Leu His 15 20 25 ttg gga agc tgt gtg att act gca aac cta caggca ata caa aag gaa 205 Leu Gly Ser Cys Val Ile Thr Ala Asn Leu Gln AlaIle Gln Lys Glu 30 35 40 45 ttt tct gag att cgg gat agt gtg tct ttg gatagg tgc tgc ttc ctt 253 Phe Ser Glu Ile Arg Asp Ser Val Ser Leu Asp ArgCys Cys Phe Leu 50 55 60 cgt cat cta gtg aga ttc tat ctg gac agg gta ttcaaa gtc tac cag 301 Arg His Leu Val Arg Phe Tyr Leu Asp Arg Val Phe LysVal Tyr Gln 65 70 75 acc cct gac cac cat acc ctg aga aag atc agc agc ctcgcc aac tcc 349 Thr Pro Asp His His Thr Leu Arg Lys Ile Ser Ser Leu AlaAsn Ser 80 85 90 ttt ctt atc atc aag aag gac ctc tca gtc tgt cat tct cacatg gca 397 Phe Leu Ile Ile Lys Lys Asp Leu Ser Val Cys His Ser His MetAla 95 100 105 tgt cat tgt ggg gaa gaa gca atg gag aaa tac aac caa attctg agt 445 Cys His Cys Gly Glu Glu Ala Met Glu Lys Tyr Asn Gln Ile LeuSer 110 115 120 125 cac ttc ata gag ttg gaa ctt cag gca gcg gtg gta aaggct ttg gga 493 His Phe Ile Glu Leu Glu Leu Gln Ala Ala Val Val Lys AlaLeu Gly 130 135 140 gaa cta ggc att ctt ctg aga tgg atg gag gag atg ctatagatgaaag 542 Glu Leu Gly Ile Leu Leu Arg Trp Met Glu Glu Met Leu 145150 tggataggct gctgagaaca ctcctgtcca agaatctcag acctcagcac catgaagaca602 tggccccagg tgctggcatt tctactcaag agttccagtc ctcagcacca cgaagatggc662 ctcaaaccac cacccctttg tgatataact tagtgctagc tatgtgtata ttatttctac722 attattggct cccttatgtg aatgccttca tgtg 756 34 154 PRT Mus musculus 34Met Lys Gly Phe Gly Leu Ala Phe Gly Leu Phe Ser Ala Val Gly Phe 1 5 1015 Leu Leu Trp Thr Pro Leu Thr Gly Leu Lys Thr Leu His Leu Gly Ser 20 2530 Cys Val Ile Thr Ala Asn Leu Gln Ala Ile Gln Lys Glu Phe Ser Glu 35 4045 Ile Arg Asp Ser Val Ser Leu Asp Arg Cys Cys Phe Leu Arg His Leu 50 5560 Val Arg Phe Tyr Leu Asp Arg Val Phe Lys Val Tyr Gln Thr Pro Asp 65 7075 80 His His Thr Leu Arg Lys Ile Ser Ser Leu Ala Asn Ser Phe Leu Ile 8590 95 Ile Lys Lys Asp Leu Ser Val Cys His Ser His Met Ala Cys His Cys100 105 110 Gly Glu Glu Ala Met Glu Lys Tyr Asn Gln Ile Leu Ser His PheIle 115 120 125 Glu Leu Glu Leu Gln Ala Ala Val Val Lys Ala Leu Gly GluLeu Gly 130 135 140 Ile Leu Leu Arg Trp Met Glu Glu Met Leu 145 150 35130 PRT Mus musculus 35 Leu Lys Thr Leu His Leu Gly Ser Cys Val Ile ThrAla Asn Leu Gln 1 5 10 15 Ala Ile Gln Lys Glu Phe Ser Glu Ile Arg AspSer Val Ser Leu Asp 20 25 30 Arg Cys Cys Phe Leu Arg His Leu Val Arg PheTyr Leu Asp Arg Val 35 40 45 Phe Lys Val Tyr Gln Thr Pro Asp His His ThrLeu Arg Lys Ile Ser 50 55 60 Ser Leu Ala Asn Ser Phe Leu Ile Ile Lys LysAsp Leu Ser Val Cys 65 70 75 80 His Ser His Met Ala Cys His Cys Gly GluGlu Ala Met Glu Lys Tyr 85 90 95 Asn Gln Ile Leu Ser His Phe Ile Glu LeuGlu Leu Gln Ala Ala Val 100 105 110 Val Lys Ala Leu Gly Glu Leu Gly IleLeu Leu Arg Trp Met Glu Glu 115 120 125 Met Leu 130 36 27 DNA Homosapiens 36 agattctatc tggacagggt attcaaa 27 37 17 DNA Homo sapiens 37gcgaggctga tctttct 17 38 25 DNA Mus musculis 38 tggcgaggct gctgatctttctcag 25 39 25 DNA Mus musculis 39 ctttatgtct ttcaaagact cagtc 25 40 26DNA Mus musculis 40 catcagaatt ttaaggacga ctgagt 26 41 25 DNA Musmusculis 41 ggtggtcagg ggtctggtag acttt 25 42 23 DNA Mus musculis 42ggtgcatatt cctggtggct aga 23 43 25 DNA Mus musculis 43 attgcagtgtaagggaatac agaga 25

What is claimed is:
 1. A method for inhibiting the growth and orproliferation of cervical cancer cells comprising bringingInterleukin-20 (IL-20) into contact with the cervical cancer cells. 2.The method of claim 1 wherein the cervical cancer cells are treated withradiation in conjunction with IL-20.
 3. The method of claim 1 whereinthe cervical cancer cells are treated with one or more additionalchemotherapeutic agents in conjunction with IL-20.
 4. The method ofclaim 3 wherein the chemotherapeutic agent is selected from the groupconsisting of bleomycin, chlorambucil, epirubicin, 5-fluorouracil,ifosfamide, mitomycin, methotrexate, vincristine, cisplatin andvinblastine.
 5. A method for treating a female mammal afflicted withcervical cancer comprising administering to said female mammal IL-20. 6.The method of claim 5 wherein the IL-20 is administered in conjunctionwith radiation.
 7. The method of claim 5 wherein the IL-20 isadministered in conjunction with a chemotherapeutic agent.
 8. The methodof claim 7 wherein the chemotherapeutic agent is selected from the groupconsisting of bleomycin, chlorambucil, epirubicin, 5-fluorouracil,ifosfamide, mitomycin, methotrexate, vincristine, cisplatin andvinblastine.
 9. A method for inhibiting the proliferation or growth ofhuman papillomavirus (HPV) comprising bringing IL-20 into contact withcells infected with HPV.
 10. The method of claim 9 wherein the IL-20 isinjected into a genital wart infected with HPV.
 11. The method of claim9 wherein the IL-20 is administered in conjunction with the consistingof interferon alpha, interferon beta, podophyllotoxin, podophyllin and5-fluorouracil, trichloroacetic acid, and imiquimod.
 12. The method ofclaim 9 wherein the IL-20 is administered in conjunction withelectrocauterization, laser, cryotherapy, or surgical excision of thecells infected with HPV.
 13. A method for treating an individualinfected with HPV comprising administering to said individual atherapeutically effective amount of IL-20.
 14. The method of claim 13wherein said individual has genital warts or lesions infected with HPVand the IL20 is injected into the lesions or genital warts infected. 15.The method of claim 14 wherein said the IL-20 is injected into saidwarts in conjunction with electrocauterization, laser, cryotherapy, orsurgical excision of the genital warts or lesions infected with HPV. 16.The method of claim 14 wherein the IL-20 is administered in conjunctionwith the consisting of interferon alpha, interferon beta,podophyllotoxin, podophyllin and 5-fluorouracil, trichloroacetic acid,and imiquimod.